Studies on the Activity of Selected Highly Lipophilic Compounds toward hGAT1 Inhibition. Part II

Nowaczyk, Alicja; Fijałkowski, Łukasz; Kowalska, Magdalena; Podkowa, Adrian; Sałat, Kinga

doi:10.1021/acschemneuro.8b00282

Cited by 9 publications

(9 citation statements)

References 67 publications

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“…It was founded approx. 6.5-7.7 Å due to separation of charged centers [55], which determines the molecule of the interaction with neurons [28]. These conformers are stabilized by intramolecular hydrogen bonds between the nitrogen atom of the amino group and hydrogen of hydroxyl group attached to an ethyl amine carbon atom [55].…”

Section: Hnetmentioning

confidence: 99%

“…A value of 5 Å determines the neuronal and glial blocking effect in selective inhibitors. Computational methods have shown that in an aqueous solution more than 94% of GABA molecules adapt a folded conformation with separation of charged centers below 5 Å [28]. GABA is transported by GAT in a somewhat folded conformation (Figure 5).…”

Section: Hgat1mentioning

confidence: 99%

“…To compare the binding strength of PRX with individual transporters, the following reference compounds were selected, SER, DA, NE and GABA. The interactions were investigated by means of docking studies of selected antidepressant compounds performed on the crystal structure of hSERT [25] and on homology modeled hNET [26], hDAT [27] and hGAT1 [28]. It is noteworthy that the sequence identity between the template (i.e., sequences with known 3D structure) and the modeled sequence is 63.3% for hNET, 52% for hDAT [29], and 47% for hGAT1 and to the best of our knowledge this is the highest available identity.…”

Section: Introductionmentioning

confidence: 99%

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Assessment of Paroxetine Molecular Interactions with Selected Monoamine and γ-Aminobutyric Acid Transporters

Kowalska

Fijałkowski

Nowaczyk

2021

IJMS

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Thus far, many hypotheses have been proposed explaining the cause of depression. Among the most popular of these are: monoamine, neurogenesis, neurobiology, inflammation and stress hypotheses. Many studies have proven that neurogenesis in the brains of adult mammals occurs throughout life. The generation of new neurons persists throughout adulthood in the mammalian brain due to the proliferation and differentiation of adult neural stem cells. For this reason, the search for drugs acting in this mechanism seems to be a priority for modern pharmacotherapy. Paroxetine is one of the most commonly used antidepressants. However, the exact mechanism of its action is not fully understood. The fact that the therapeutic effect after the administration of paroxetine occurs after a few weeks, even if the levels of monoamine are rapidly increased (within a few minutes), allows us to assume a neurogenic mechanism of action. Due to the confirmed dependence of depression on serotonin, norepinephrine, dopamine and γ-aminobutyric acid levels, studies have been undertaken into paroxetine interactions with these primary neurotransmitters using in silico and in vitro methods. We confirmed that paroxetine interacts most strongly with monoamine transporters and shows some interaction with γ-aminobutyric acid transporters. However, studies of the potency inhibitors and binding affinity values indicate that the neurogenic mechanism of paroxetine’s action may be determined mainly by its interactions with serotonin transporters.

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Section: Hnetmentioning

confidence: 99%

Section: Hgat1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Assessment of Paroxetine Molecular Interactions with Selected Monoamine and γ-Aminobutyric Acid Transporters

Kowalska

Fijałkowski

Nowaczyk

2021

IJMS

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“…Previously, various antagonists of hGAT1, including nipecotic acid, guvacine, proline, pyrrolidine, azetidine and THPO derivatives (Dalby, 2000; Andersen et al, 2001; Clausen et al, 2005; Fülep et al, 2006; Faust et al, 2010; Hellenbrand et al, 2016; Schmidt, Höfner & Wanner, 2017; Lutz et al, 2018; Tóth, Höfner & Wanner, 2018), have been synthesized and pharmacologically tested and optimized using structure–activity relationship (SAR) data. Additionally, several ligand-based strategies including 2D QSAR (Jurik et al, 2013), CoMFA (Zheng et al, 2006) and pharmacophore models (Hirayama, Díez-Sampedro & Wright, 2001; Nowaczyk et al, 2018) have been developed to optimize small molecule inhibitors against hGAT1. However, most of these studies were class specific, focusing on nipecotic acid derivatives (Petrera et al, 2015), Tiagabine analogs (Jurik et al, 2015) and triarylnipecotic acid derivatives (Dhar et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of γ-aminobutyric acid transporter 1 (GAT1) inhibitors

Zafar¹,

Jabeen²

2019

PeerJ

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BackgroundThe γ-aminobutyric acid (GABA) transporter GAT1 is involved in GABA transport across the biological membrane in and out of the synaptic cleft. The efficiency of this Na+ coupled GABA transport is regulated by an electrochemical gradient, which is directed inward under normal conditions. However, in certain pathophysiological situations, including strong depolarization or an imbalance in ion homeostasis, the GABA influx into the cytoplasm is increased by re-uptake transport mechanism. This mechanism may lead to extra removal of extracellular GABA which results in numerous neurological disorders such as epilepsy. Thus, small molecule inhibitors of GABA re-uptake may enhance GABA activity at the synaptic clefts.MethodsIn the present study, various GRID-independent molecular descriptor (GRIND) models have been developed to shed light on the 3D structural features of human GAT1 (hGAT1) inhibitors using nipecotic acid and N-diarylalkenyl piperidine analogs. Further, a binding hypothesis has been developed for the selected GAT1 antagonists by molecular docking inside the binding cavity of hGAT1 homology model.ResultsOur results indicate that two hydrogen bond acceptors, one hydrogen bond donor and one hydrophobic region at certain distances from each other play an important role in achieving high inhibitory potency against hGAT1. Our docking results elucidate the importance of the COOH group in hGAT1 antagonists by considering substitution of the COOH group with an isoxazol ring in compound 37, which subsequently leads to a three order of magnitude decrease in biological activity of 37 (IC50 = 38 µM) as compared to compound 1 (IC50 = 0.040 µM).DiscussionOur docking results are strengthened by the structure activity relationship of the data series as well as by GRIND models, thus providing a significant structural basis for understanding the binding of antagonists, which may be useful for guiding the design of hGAT1 inhibitors.

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“…Previously, various antagonists of hGAT1, including nipecotic acid, guvacine, proline, pyrrolidine, azetidine and THPO derivatives (Dalby, 2000;Andersen et al, 2001;Clausen et al, 2005;Fülep et al, 2006;Faust et al, 2010;Hellenbrand et al, 2016;Schmidt et al, 2017;Lutz et al, 2018;Tóth et al, 2018), have been synthesized and pharmacologically tested and optimized using SAR data. Additionally, several ligand-based strategies including 2D QSAR (Jurik et al, 2013), CoMFA (Zheng et al, 2006) and pharmacophore models (Hirayama et al, 2001;Nowaczyk et al, 2018) have been developed to optimize small molecule inhibitors against hGAT1. However, most of these studies were class specific, focusing on nipecotic acid derivatives (Petrera et al, 2015), Tiagabine analogs (Jurik et al, 2015) and triarylnipecotic acid derivatives (Dhar et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Peer Review #1 of "GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of γ-aminobutyric acid transporter 1 (GAT1) inhibitors (v0.1)"

2019

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Background: The γ-aminobutyric acid (GABA) transporter GAT1 is involved in GABA transport across the biological membrane in and out of the synaptic cleft. The efficiency of this Na + coupled GABA transport is regulated by an electrochemical gradient, which is directed inward under normal conditions. However, in certain pathophysiological situations, including strong depolarization or an imbalance in ion homeostasis, the GABA influx into the cytoplasm is increased by re-uptake transport mechanism. This mechanism may lead to extra removal of extracellular GABA which results in numerous neurological disorders such as epilepsy. Thus, small molecule inhibitors of GABA re-uptake may enhance GABA activity at the synaptic clefts. Methods: In the present study, various GRID Independent Molecular Descriptor (GRIND) models have been developed to shed light on the 3D structural features of hGAT1 inhibitors using nipecotic acid and N-diarylalkenyl piperidine analogs. Further, a binding hypothesis has been developed for the selected GAT1 antagonists by molecular docking inside the binding cavity of human GAT1 (hGAT1) homology model. Results: Our results indicate that two hydrogen bond acceptors, one hydrogen bond donor and one hydrophobic region at certain distances from each other play an important role in achieving high inhibitory potency against hGAT1. Our docking results elucidate the importance of the COOH group in hGAT1 antagonists by considering substitution of the COOH group with an isoxazol ring in compound 37, which subsequently leads to a three order of magnitude decrease in biological activity of 37 (IC 50 = 38 µM) as compared to compound 1 (IC 50 = 0.040 µM). Discussion: Our docking results are strengthened by the structure activity relationship (SAR) of the data series as well as by GRIND models, thus providing a significant structural basis for understanding the binding of antagonists, which may be useful for guiding the design of hGAT1 inhibitors.

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Studies on the Activity of Selected Highly Lipophilic Compounds toward hGAT1 Inhibition. Part II

Cited by 9 publications

References 67 publications

Assessment of Paroxetine Molecular Interactions with Selected Monoamine and γ-Aminobutyric Acid Transporters

Assessment of Paroxetine Molecular Interactions with Selected Monoamine and γ-Aminobutyric Acid Transporters

GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of γ-aminobutyric acid transporter 1 (GAT1) inhibitors

Peer Review #1 of "GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of γ-aminobutyric acid transporter 1 (GAT1) inhibitors (v0.1)"

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